mTOR inhibitors reduce enteropathy, intestinal bleeding and colectomy rate in patients with juvenile polyposis of infancy with PTEN-BMPR1A deletion.
Journal
Human molecular genetics
ISSN: 1460-2083
Titre abrégé: Hum Mol Genet
Pays: England
ID NLM: 9208958
Informations de publication
Date de publication:
26 06 2021
26 06 2021
Historique:
received:
13
01
2021
revised:
28
03
2021
accepted:
30
03
2021
pubmed:
7
4
2021
medline:
8
4
2022
entrez:
6
4
2021
Statut:
ppublish
Résumé
Ultra-rare genetic disorders can provide proof of concept for efficacy of targeted therapeutics and reveal pathogenic mechanisms relevant to more common conditions. Juvenile polyposis of infancy (JPI) is caused by microdeletions in chromosome 10 that result in haploinsufficiency of two tumor suppressor genes: phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and bone morphogenetic protein receptor type IA (BMPR1A). Loss of PTEN and BMPR1A results in a much more severe phenotype than deletion of either gene alone, with infantile onset pan-enteric polyposis and a high mortality rate. No effective pharmacological therapy exists. A multi-center cohort analysis was performed to characterize phenotype and investigate the therapeutic effect of mammalian target of rapamycin (mTOR) inhibition (adverse events, disease progression, time to colectomy and mortality) in patients with JPI. Among 25 JPI patients identified (mean age of onset 13 months), seven received mTOR inhibitors (everolimus, n = 2; or sirolimus, n = 5). Treatment with an mTOR inhibitor reduced the risk of colectomy (hazard ratio = 0.27, 95% confidence interval = 0.07-0.954, P = 0.042) and resulted in significant improvements in the serum albumin level (mean increase = 16.3 g/l, P = 0.0003) and hemoglobin (mean increase = 2.68 g/dl, P = 0.0077). Long-term mTOR inhibitor treatment was well tolerated over an accumulated follow-up time of 29.8 patient years. No serious adverse events were reported. Early therapy with mTOR inhibitors offers effective, pathway-specific and personalized treatment for patients with JPI. Inhibition of the phosphoinositol-3-kinase-AKT-mTOR pathway mitigates the detrimental synergistic effects of combined PTEN-BMPR1A deletion. This is the first effective pharmacological treatment identified for a hamartomatous polyposis syndrome.
Identifiants
pubmed: 33822054
pii: 6209145
doi: 10.1093/hmg/ddab094
pmc: PMC8804886
doi:
Substances chimiques
MTOR Inhibitors
0
MTOR protein, human
EC 2.7.1.1
TOR Serine-Threonine Kinases
EC 2.7.11.1
BMPR1A protein, human
EC 2.7.11.30
Bone Morphogenetic Protein Receptors, Type I
EC 2.7.11.30
PTEN Phosphohydrolase
EC 3.1.3.67
PTEN protein, human
EC 3.1.3.67
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1273-1282Subventions
Organisme : NIHR Oxford Biomedical Research Centre
Informations de copyright
© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
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